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Recent studies have demonstrated that combining TMZ with natural compounds can enhance therapeutic efficacy through synergistic mechanisms and reduce systemic toxicity. In this study, the adjuvant potential of troxerutin (TROX), a natural flavonoid present found in tea, coffee, cereals, fruits and vegetables, and known for its antioxidant and anti\u2010inflammatory properties, was evaluated in an in\u00a0vitro model of human U87 cells. The TROX\u2013TMZ combination showed a significant synergistic effect, effectively reducing cell viability, clonogenic capacity, migration and epithelial\u2010mesenchymal transition (EMT), as well as promoting apoptosis. The combined treatment also modulated oxidative stress and inflammation by activating the KEAP1\/NRF2 axis, resulting in increased levels of HO\u20101, GSH and SOD1, and decreased ROMO1, ROS, nitrites and pro\u2010inflammatory cytokines (IL\u20106, TNF\u2010\u03b1 and IL\u20101\u03b2). These effects were also confirmed in three\u2010dimensional models (spheroids), suggesting that the combination exerts significant antitumor activity. These results indicate that TROX could represent an effective adjuvant in the treatment of GBM, providing a novel therapeutic strategy to potentiate the antitumor effects of TMZ.<\/jats:p>","DOI":"10.1111\/jcmm.70862","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T16:54:15Z","timestamp":1759510455000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Troxerutin Potentiated Temozolomide Induced Antitumor Effect in <scp>2D<\/scp> and <scp>3D<\/scp> Glioblastoma Models"],"prefix":"10.1111","volume":"29","author":[{"given":"Deborah","family":"Mannino","sequence":"first","affiliation":[{"name":"Research Operative Unit of Neuropharmacology and Translational Neurosciences Oasi Research Institute  Troina Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elsa","family":"Calcaterra","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, 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